The Rat Diabetes Susceptibility Locus Iddm4 and at Least One Additional Gene Are Required for Autoimmune Diabetes Induced by Viral Infection

  1. Elizabeth P. Blankenhorn1,
  2. Lucy Rodemich1,
  3. Cristina Martin-Fernandez1,
  4. Jean Leif2,
  5. Dale L. Greiner2 and
  6. John P. Mordes2
  1. 1Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania
  2. 2Department of Medicine, University of Massachusetts, Worcester, Massachusetts
  1. Address correspondence and reprint requests to Dr. John Mordes, Diabetes Division, 373 Plantation St., Biotech 2, Suite 218, Worcester, MA 01605. E-mail: john.mordes{at}


BBDR rats develop autoimmune diabetes only after challenge with environmental perturbants. These perturbants include polyinosinic:polycytidylic acid (poly I:C, a ligand of toll-like receptor 3), agents that deplete regulatory T-cell (Treg) populations, and a non–β-cell cytopathic parvovirus (Kilham rat virus [KRV]). The dominant diabetes susceptibility locus Iddm4 is required for diabetes induced by treatment with poly I:C plus Treg depletion. Iddm4 is penetrant in congenic heterozygous rats on the resistant WF background and is 79% sensitive and 80% specific as a predictor of induced diabetes. Surprisingly, an analysis of 190 (BBDR × WF)F2 rats treated with KRV after brief exposure to poly I:C revealed that the BBDR-origin allele of Iddm4 is necessary but not entirely sufficient for diabetes expression. A genome scan identified a locus on chromosome 17, designated Iddm20, that is also required for susceptibility to diabetes after exposure to KRV and poly I:C (logarithm of odds score 3.7). These data suggest that the expression of autoimmune diabetes is a complex process that requires both major histocompatibility complex genes that confer susceptibility and additional genes such as Iddm4 and Iddm20 that operate only in the context of specific environmental perturbants, amplifying the immune response and the rate of disease progression.


  • Additional information for this article can be found in an online appendix at

    • Accepted December 22, 2005.
    • Received December 1, 2004.
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